Pregestational diabetes significantly increases the risk of NTDs, also known as diabetic embryopathy. There are 3-10 times more NTDs in offspring of diabetic mothers than those of nondiabetic mothers (3, 9, 32). Because optimal glycemic control is difficult to achieve and maintain, and even transient exposure to diabetes can cause NTDs, maternal diabetes-induced NTDs are significant health problems for both the mother and her child. The seriousness of these relationships is emphasized by the upsurge in diabetic pregnancies: nearly 3 million American women and 70 million women worldwide of reproductive age (18-44 years) have diabetes today, and this number is expected double by 2030. Although diabetes mellitus is a complex metabolic disease, hyperglycemia is the sole mediator of diabetes teratogenicity. Indeed, clinical studies have revealed a strong correlation between the degree of maternal hyperglycemia and the rate and severity of birth defects (14, 26). When whole rodent embryos are cultured in high concentrations of glucose, high glucose induces NTDs similar to those observed in human fetuses exposed to maternal diabetes (48).
An internationally-accepted rodent model of type 1 diabetes, which mimics the human condition seen in type 1 and type 2 maternal diabetes, can be used to study the pathogenesis of maternal diabetes-induced NTDs. Such studies (1, 13, 20, 21, 22, 30, 33) have revealed that cellular stress, including oxidative stress and endoplasmic reticulum (ER) stress, and enhanced neural progenitor apoptosis play central roles in the induction of NTDs by maternal diabetes. However, the molecular intermediates downstream of hyperglycemia remain elusive.
Autophagy, also referred as macroautophagy, is an intracellular process that degrades dysfunctional proteins and damaged cellular organelles, including ER and mitochondria. Autophagy is highly active in, and essential for, early embryonic development (39). The precise role of autophagy in early embryogenesis may be explained by its clearance of unnecessary cellular components, which, thus, facilitates remodeling during differentiation (27). Autophagy is initiated by the formation of a double-membrane structure, the autophagosome (12). At least fourteen genes are essential for autophagosome formation (27). Multiple lines of indirect evidence suggest that autophagy plays a role in diabetic embryopathy. First, diminished autophagy resulting from deletion of the autophagy/beclin-1 regulator 1 (Ambra1) gene induces neural progenitor apoptosis and NTDs (11) reminiscent of those observed in diabetic embryopathy. Second, both oxidative stress and ER stress, two central players in diabetic embryopathy, regulates autophagy (6). Third, autophagy can act as either a pro-survival or pro-apoptotic mediator under physiological and pathological conditions (19). Finally, dysfunctional proteins (43) and damaged cellular organelles, such as mitochondria (49) and ER (22), accumulate in cells of neurulation-stage embryos exposed to maternal diabetes.
Folate supplements are able to prevent about 70% of NTDs in humans (42) and reduce maternal diabetes-induced NTDs in animal models (45). However, recent studies suggest that high maternal folate supplementation during pregnancy may increase the risk of breast cancer (25) and inflammatory bowel diseases (35) in offspring. Studies have shown that inositol can prevent some of the folate-resistant NTDs (15). Like folate, inositol is an intracellular signaling molecule that regulates various cellular processes (46), and, thus, may adversely affect the offspring of diabetic mothers in the long term. Furthermore, inositol- and folate-resistant NTDs have been observed in mouse models (38).
In view of the predicted increase in diabetic embryopathy and the dearth of acceptable means for preventing the condition, the development of accessible, convenient, and effective prevention strategies against maternal diabetes-induced NTDs are urgently needed.